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An ultrapotent synthetic nanobody neutralizes SARS-CoV-2 by stabilizing inactive Spike.

  • Author(s): Schoof, Michael
  • Faust, Bryan
  • Saunders, Reuben A
  • Sangwan, Smriti
  • Rezelj, Veronica
  • Hoppe, Nick
  • Boone, Morgane
  • Billesbølle, Christian B
  • Puchades, Cristina
  • Azumaya, Caleigh M
  • Kratochvil, Huong T
  • Zimanyi, Marcell
  • Deshpande, Ishan
  • Liang, Jiahao
  • Dickinson, Sasha
  • Nguyen, Henry C
  • Chio, Cynthia M
  • Merz, Gregory E
  • Thompson, Michael C
  • Diwanji, Devan
  • Schaefer, Kaitlin
  • Anand, Aditya A
  • Dobzinski, Niv
  • Zha, Beth Shoshana
  • Simoneau, Camille R
  • Leon, Kristoffer
  • White, Kris M
  • Chio, Un Seng
  • Gupta, Meghna
  • Jin, Mingliang
  • Li, Fei
  • Liu, Yanxin
  • Zhang, Kaihua
  • Bulkley, David
  • Sun, Ming
  • Smith, Amber M
  • Rizo, Alexandrea N
  • Moss, Frank
  • Brilot, Axel F
  • Pourmal, Sergei
  • Trenker, Raphael
  • Pospiech, Thomas
  • Gupta, Sayan
  • Barsi-Rhyne, Benjamin
  • Belyy, Vladislav
  • Barile-Hill, Andrew W
  • Nock, Silke
  • Liu, Yuwei
  • Krogan, Nevan J
  • Ralston, Corie Y
  • Swaney, Danielle L
  • García-Sastre, Adolfo
  • Ott, Melanie
  • Vignuzzi, Marco
  • QCRG Structural Biology Consortium
  • Walter, Peter
  • Manglik, Aashish
  • et al.
Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus enters host cells via an interaction between its Spike protein and the host cell receptor angiotensin-converting enzyme 2 (ACE2). By screening a yeast surface-displayed library of synthetic nanobody sequences, we developed nanobodies that disrupt the interaction between Spike and ACE2. Cryo-electron microscopy (cryo-EM) revealed that one nanobody, Nb6, binds Spike in a fully inactive conformation with its receptor binding domains locked into their inaccessible down state, incapable of binding ACE2. Affinity maturation and structure-guided design of multivalency yielded a trivalent nanobody, mNb6-tri, with femtomolar affinity for Spike and picomolar neutralization of SARS-CoV-2 infection. mNb6-tri retains function after aerosolization, lyophilization, and heat treatment, which enables aerosol-mediated delivery of this potent neutralizer directly to the airway epithelia.

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